The Roles of CCR9/CCL25 in Inflammation and Inflammation-Associated Diseases - Frontiers
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REVIEW
published: 19 August 2021
doi: 10.3389/fcell.2021.686548
The Roles of CCR9/CCL25 in
Inflammation and
Inflammation-Associated Diseases
Xue Wu 1,2† , Meng Sun 3† , Zhi Yang 1,2† , Chenxi Lu 1,2† , Qiang Wang 1 , Haiying Wang 1 ,
Chao Deng 4 , Yonglin Liu 1* and Yang Yang 1,2* †
1
Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China,
2
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences,
Northwest University, Xi’an, China, 3 Department of Cardiology, The First Hospital of Shanxi Medical University, Taiyuan,
China, 4 Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
Chemokine is a structure-related protein with a relatively small molecular weight, which
can target cells to chemotaxis and promote inflammatory response. Inflammation
Edited by:
InKyeom Kim, plays an important role in aging. C-C chemokine receptor 9 (CCR9) and its ligand
Kyungpook National University, C-C chemokine ligand 25 (CCL25) are involved in the regulating the occurrence
South Korea
and development of various diseases, which has become a research hotspot. Early
Reviewed by:
Dwijendra K. Gupta,
research analysis of CCR9-deficient mouse models also confirmed various physiological
Jai Prakash Vishwavidyalaya, India functions of this chemokine in inflammatory responses. Moreover, CCR9/CCL25 has
Olga Scudiero,
been shown to play an important role in a variety of inflammation-related diseases,
University of Naples Federico II, Italy
such as cardiovascular disease (CVD), rheumatoid arthritis, hepatitis, inflammatory
*Correspondence:
Yonglin Liu bowel disease, asthma, etc. Therefore, the purpose of this review gives an overview
yonglinliusm@163.com of the recent advances in understanding the roles of CCR9/CCL25 in inflammation
Yang Yang
yang200214yy@163.com
and inflammation-associated diseases, which will contribute to the design of future
† These authors have contributed experimental studies on the potential of CCR9/CCL25 and advance the research of
equally to this work CCR9/CCL25 as pharmacological inflammatory targets.
Specialty section: Keywords: chemokine, CCR9, CCL25, autoimmune, inflammatory disease
This article was submitted to
Cellular Biochemistry,
a section of the journal INTRODUCTION
Frontiers in Cell and Developmental
Biology Chemokines are a large family of small cytokines and generally have low molecular weight ranging
Received: 12 April 2021 from 7 to 15 kDa (Palomino and Marti, 2015). Chemokines can interact with different chemokine
Accepted: 23 July 2021 receptors that control the residence and migration of immune cells. When the body is stimulated
Published: 19 August 2021 by antigen, chemokines can be secreted by various cells such as endothelial and dendritic cells
Citation: (DCs) (Vassilatis et al., 2003). Currently, more than 50 chemokines have been discovered, which
Wu X, Sun M, Yang Z, Lu C, can be divided into four categories according to the position of two cysteines at the N-terminus:
Wang Q, Wang H, Deng C, Liu Y and C subfamily, CC subfamily, CXC subfamily, and CX3C subfamily (Figure 1; Bleul et al., 1996).
Yang Y (2021) The Roles
Moreover, according to the expression of chemokines and their functions in the immune system,
of CCR9/CCL25 in Inflammation
and Inflammation-Associated
chemokines can be also divided into homeostatic and inflammatory chemokines (Table 1; Moser
Diseases. et al., 2004). Chemokines expression is regulated via a variety of factors such as interleukin (IL)-10
Front. Cell Dev. Biol. 9:686548. and glucocorticoids, which can inhibit the secretion of chemokines, while IL-1 and tumor necrosis
doi: 10.3389/fcell.2021.686548 factor (TNF)-α can increase chemokines expression (Cocchi et al., 1995; Oberlin et al., 1996;
Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 August 2021 | Volume 9 | Article 686548
Wu et al. Roles of CCR9/CCL25 in Inflammation
Zlotnik and Yoshie, 2012). The chemokine receptor is a diseases and promote inflammatory responses. Over the years,
G-protein coupled receptor of the seven-transmembrane the role of CCR9/CCL25 in inflammation and related diseases
receptor family, which contains seven transmembrane segments has become increasingly clearness, including cardiovascular
and is widely expressed on white blood cells surface derived disease (CVD), hepatitis, arthritis (Yokoyama et al., 2014),
from bone marrow such as neutrophils and macrophages inflammatory bowel disease (Kalindjian et al., 2016), and asthma.
(Schulz et al., 2016). In addition, chemokine receptors have This study provides abundant evidence that CCR9/CCL25 can
also been shown to be expressed in epithelial cells, vascular be a potential target for a variety of inflammatory diseases.
endothelial cells, and other tissue cells. The combination of Therefore, the focus of this review is to evaluate the latest
chemokines and their corresponding receptors can involve findings on the role of CCR9/CCL25 in inflammatory disease.
in normal body development, and also participate in various The structure and physiological function of CCR9/CCL25 were
pathological and physiological processes such as leukocyte briefly introduced. The various roles of CCR9/CCL25 in the
activation, angiogenesis, aging, breast cancer resistance, and development of inflammatory disease were described (Figure 2),
autoimmune diseases (Zhong et al., 2015). and some different insights were put forward concerning the
C-C chemokine ligand 25 (CCL25) is also considered a thymus CCR9/CCL25 pathway.
expressed chemokine, and the gene is located on chromosome
19p13.2 (Figure 1; Qiuping et al., 2004). Tu et al. (2016)
confirmed that CCL25 is mainly expressed in the thymus and
intestinal epithelium, and also produced by vascular endothelial CCR9 AND CCL25 EXPRESSION IN
cells and other parenchymal cells, which can migrate immature TISSUE
T cells into the thymus to mature and release (Table 1). C-C
chemokine receptor 9 (CCR9) was discovered in 1996 as a G Vicari et al. (1997) isolated CCL25 cDNA from the thymus of
protein-coupled receptors expressed on the cell membrane of recombinase activation gene-1 (RAG-1) deficient mice and were
dendritic cell, neutrophils, lymphocytes, monocyte macrophages, designated thymus-expressed chemokine (TECK). Moreover,
and vascular endothelial cells (Yu and Stamenkovic, 2000). they also found that CCL25 appeared weak sequence homology
However, in the 3 years after the discovery of CCR9, its ligand has to other members of the CC chemokine family and located
not been found, so it was once called "orphan receptor." It was not on mouse chromosome 8 (Vicari et al., 1997). Besides the
until 1999 that CCL25 was found to be one-to-one combined with thymus, mRNA encoding CCL25 was detected at substantial
CCR9 (Zaballos et al., 1999). CCR9 belongs to the β-chemokine levels in the small intestine and at low levels in the liver (Vicari
receptor family, and its gene is located on chromosome 3 p21.31 et al., 1997; Zabel et al., 1999; Kunkel et al., 2000). However,
(Tu et al., 2016). CCR9 is mainly distributed in immature T studies found that CCL25 is highly expressed in the small
lymphocytes and intestinal cells surface, and after binding to its intestinal epithelium and thymus, which can regulate trafficking
specific ligands, plays a key role in T lymphocyte development of gut-specific memory/effector T cells via upregulation of
and tissue-specific homing (Wermers et al., 2011; Wu et al., the integrin homing receptor α47 and CCR9 (Stenstad et al.,
2014). Further study found that CCL25 promoted proliferation 2006; Wurbel et al., 2000, 2007). Meanwhile, the source of
and chemotaxis of inflammatory cells that expressed its specific CCL25 in the thymus was determined to be thymic dendritic
receptor CCR9 (Igaki et al., 2018). cells; in contrast, bone marrow-derived dendritic cells do not
CCR9 and CCL25 are members of the CC subfamily of express CCL25. The murine CCL25 recombinant protein showed
chemokines that are involved in a variety of inflammatory chemotactic activity for activated macrophages, dendritic cells,
and thymocytes. These research results fully demonstrated that
CCL25 represents a novel thymic dendritic cell-specific CC
chemokine that is possibly involved in T cell development.
Within the intestines of normal mice, CCL25 expression was
highest in the proximal small intestine, lowest in the distal small
bowel, and no or almost no expression in the colon (Svensson
et al., 2002; Rivera-Nieves et al., 2006; Stenstad et al., 2007;
Wermers et al., 2011; Wurbel et al., 2011).
In circulating white blood cells, CCR9 expression is limited
to activated B cells and a certain proportion of CD4 and CD8 T
cells (Zabel et al., 1999; Kunkel et al., 2000; Papadakis et al., 2000,
2001, 2003). CCR9 has been identified in plasmacytoid dendritic
cells in mice, but there is a lack of relevant data in humans
(Wendland et al., 2007; Hadeiba et al., 2012). Similarly, despite
the fact that a few papers describe the expression of CCR9 on
mouse macrophages, there is a lack of human data (Nakamoto
et al., 2012). In the peripheral tissues, CCR9+ cells are mostly
FIGURE 1 | Structure of members of the chemokine family. concentrated in colon, thymus, and small intestine (Zabel et al.,
1999; Kunkel et al., 2000; Papadakis et al., 2000). Intraepithelial
Frontiers in Cell and Developmental Biology | www.frontiersin.org 2 August 2021 | Volume 9 | Article 686548Wu et al. Roles of CCR9/CCL25 in Inflammation
TABLE 1 | Classification, structural features, function, and location of the chemokine family members.
Family Structural features Function Location Chemokines
CXC The CXC family has a single amino acid residue CXC chemokines have the highest ability to attract 4q12-13 CXCL1-8
in between the first two cysteines. neutrophils and monocytes. 4q21.21 CXCL9-11
10q11.1 CXCL12
4q21 CXCL13
5p31 CXCL14
17p13 CXCL1
CC The CC chemokine family has the first two CC chemokines are mainly responsible for the 17q11.2 CCL1-15
cysteine residues adjacent to each other. recruitment of lymphocytes. 7q11.23 CCL16
16q13 CCL17
17q11.2 CCL18
9q13 CCL19
2q33-3 CCL20
9q13 CCL21
16q13 CCL22 CCL23
11q11.2 CCL24
7q11.23 CCL25
19p13.2 CCL26
7q11.23 CCL27
9q13 CCL28
5q
C The C family there is only one cysteine residue C chemokine has chemotactic activity for lymphocytes, 1q23 XCL1-2
and only one disulfide chain. CD4+ and CD8+ T cells, and NK cells.
CX3C The CX3C chemokine family three amino acid CX3C chemokines can induce chemotaxis of 16q13 CX3CL1
residues separate the first two cysteines. monocytes and cytotoxic T cells.
The spacing of two conserved cysteine residues at the N-terminus determines the nomenclature and classification of the chemokine family members; in CXC, CC, C, and
CX3C chemokines. Moreover, according to the classification of chemokines, these four types also have different functions and localizations.
lymphocytes are mainly CD8+ , most of which express CCR9 rate and left ventricular dysfunction, reduce infarct size, and
surface (Zabel et al., 1999; Kunkel et al., 2000). improve cardiac function after MI. In addition, abolish of
CCR9 in the mouse MI heart significantly increased Bcl-2
expression, while the expression of Bax and cleaved caspase
THE ROLE OF CCR9/CCL25 IN 3 was remarkably reduced, thereby attenuating the apoptosis
INFLAMMATORY DISEASES of cardiomyocytes. Inflammation is considered the most vital
pathological response to damage and repair, and abolish of CCR9
Inflammation underlies many physiological and pathological can decrease pro-inflammatory cytokines mRNA levels (IL-6,
processes. In particular, chronic inflammation is attributed to IL-1β, and TNF-α) and suppress the inflammatory response
the pathophysiological basis of various modern diseases. Of after MI. In addition, CCR9 is involved in structural remodeling
note, inflammatory diseases are characterized by wide coverage, mainly by interfering with NF-κB and MAPK signaling pathways
complex pathogenesis, and large difference in prognosis (Guo (Figure 2). These results confirmed that CCR9/CCL25 may exert
et al., 2015). Therefore, we mainly focus on the effect of a positive role in MI (Huang et al., 2016).
CCR9/CCL25 in inflammatory diseases as well as elaborate on Heart failure is the leading cause of death in many countries,
their mechanism of action in related diseases. particularly in an aging population (Kumarswamy and Thum,
2013). Currently, heart failure is widely recognized as a clinical
Cardiovascular Disease syndrome caused by cardiac hypertrophy and remodeling that
Cardiovascular disease, also known as circulatory disease, is a involves changes of structural and functional in the left ventricle
series of diseases involving the circulatory system, including the (Zhang et al., 2014). Study found that CCR9 protein levels
heart and blood vessels, which have always been at the forefront have significantly increased in failing human hearts and mice
of human major causes of death (Jokinen, 2015). Heart failure, or cardiomyocyte hypertrophy model. The loss of CCR9 in
cardiac hypertrophy, and atherosclerosis are belong to CVD and mice can reduce the hypertrophy caused by pressure overload.
are also a chronic vascular inflammatory disease, which have The results show that heart weight/body weight, lung weight,
high morbidity, high mortality, and high disability rate, and thus, and heart weight/tibia length ratios of CCR9-deficient mice
seriously threaten human health (Van Camp, 2014). are significantly lower than those of the control group. And
In CCR9 knockout CCR9+/+ mice, surgical ligation of the aortic banding treated CCR9-deficient mice were characterized
left anterior descending coronary artery caused myocardial by decreased Left ventricular (LV) end diastolic and systolic
infarction (MI), and found that the expression of CCR9 in diameters and increased fractional shortening, demonstrating
the heart of mice was significantly up-regulated after MI. smaller LV dimensions and elevated systolic function. Moreover,
Down-regulation of CCR9 expression can improve survival the hypertrophic response of the CCR9-deficient mice was
Frontiers in Cell and Developmental Biology | www.frontiersin.org 3 August 2021 | Volume 9 | Article 686548Wu et al. Roles of CCR9/CCL25 in Inflammation
FIGURE 2 | Schematic diagram illustrating the regulation of molecular mechanisms of CCR9/CCL25 in inflammatory diseases. CCR9/CCL25 exerts multiple effects
in a variety of inflammatory diseases by regulating molecular mechanisms, such as molecules associated with apoptosis and inflammation. CCR9, C-C chemokine
receptor 9; CCL25, C-C chemokine ligand 25; Bcl-2, B-cell lyumphoma-2; Bax, Bcl-2 Associated X-protein; IL-6, interleukin-6; IL-1β, interleukin-1β; TNF-α, tumor
necrosis factor-α; mTOR, mechanistic target of rapamycin; GSK3β, glycogen synthase kinase 3-beta; p70S6K, p70 S6 kinase; IL-10, interleukin-10; MMP3, matrix
metalloproteinase-3; TNF-β, tumor necrosis factor-β; IL-17, interleukin-17; CCL11, C-C chemokine ligand 11; Th1/Th17, helper T1/helper T17; IFN-γ,
interferon-gamma; IL-2, interleukin-2; IL-17A, interleukin-17A.
remarkably attenuated compared with controls, and these of CCR9/CCL25 in other CVD has not been reported, so further
animals manifested decreased heart size and cardiomyocyte research is needed.
cross sectional area as well as alleviation of interstitial fibrosis.
The mRNA levels of hypertrophic and fibrotic markers were Hepatitis
also reduced significantly in the CCR9 deficient mice. Notably, Hepatitis usually refers to various pathogenic factors, including
overexpression of CCR9 in mice reversed the result of the appeal parasites, viruses, drugs, bacteria, and autoimmune factors, which
(Xu et al., 2016). In terms of mechanism, they further found cause damage to liver cells and functions, thereby causing a series
that the expression levels of MAPK lack difference between the of uncomfortable symptoms of the body and abnormal liver
two groups, while the phosphorylation levels of AKT/protein function indicators (Crispe, 2003; Thomson and Knolle, 2010;
kinase B and downstream effectors (mTOR, GSK3b, and p70S6K) Linder and Malani, 2017).
were remarkably reduced in CCR9 knockout mice and increased As well known, various immune cells in the liver involve in
in CCR9 transgenic mice after aortic surgery (Figure 2). These the pathogenesis of liver diseases. Inflammatory macrophages
results suggested that CCR9 could promote hypertrophy mainly play a key role in liver injury and then liver fibrosis and
due to the protein kinase B mammalian target of the rapamycin canceration. Nakamoto et al. (2012) previous research suggests
GSK-3β signaling cascade, rather than through the MAPK that CCR9+ inflammatory macrophage triggers acute liver
signaling pathway, which indicates that CCR9 can be used as injury by interacting with helper T 1 (Th1) cells in the
a new regulator of myocardial hypertrophy and may provide a inflamed liver. Subsequently, they found that macrophages
novel therapeutic target for suppressing myocardial hypertrophy expressing CCR9+ CD11b+ aggravated liver damage through
in the future (Xu et al., 2016). production of inflammatory cytokines and the promotion of Th1
In conclusion, the knockout of CCR9/CCL25 serves as a cell development during the concanavalin A-induced murine
novel modulator of pathological progression for inhibiting the acute liver injury and human acute hepatitis (Nakamoto,
development of MI and heart failure (Table 2). However, the role 2016). Further analysis using liver-shielded radiation and
Frontiers in Cell and Developmental Biology | www.frontiersin.org 4 August 2021 | Volume 9 | Article 686548Wu et al. Roles of CCR9/CCL25 in Inflammation
TABLE 2 | The role of CCR9/CCL25 in inflammatory-associated diseases.
Inflammation Expression of Model Effect of CCR9/CCL25 Outcome References
disease CCR9 or CCL25
Myocardial Increased CCR9 Model of myocardial Down-regulation of CCR9 expression can improve CCR9/CCL25 axis may play an Huang et al.,
infarction infarction induced by survival rate, left ventricular dysfunction, cardiac important role in inflammatory cell 2016
ligation of left anterior function, reduce infarct size, meanwhile, infiltration and cardiac remodeling after
descending coronary significantly attenuate the apoptosis of myocardial infarction.
artery of CCR9−/− cardiomyocytes, and inhibit the inflammatory
and CCR9+/+ mice response after myocardial infarction.
Hepatitis – Concanavalin Macrophages expressing CCR9+ CD11b+ Inflammatory macrophages originated Amiya et al.,
A-induced murine aggravated liver damage through production of from bone marrow and became locally 2016;
acute liver injury and inflammatory cytokines and the promotion of Th1 differentiated and proliferated by Nakamoto,
human acute hepatitis cell development. interaction with hepatic stellate cells 2016
via knocking out CCR9 gene during
acute liver injury.
Rheumatoid Increased CCR9 In the synovium of RA Stimulation with CCL25 increased IL-6 and MMP-3 The interaction between CCL25 and Yokoyama
arthritis and CCL25 and non-RA patients production from RA fibroblast-like synoviocytes, CCR9 may promote cell infiltration et al., 2014
and also increased IL-6 and TNF-α production from and production of inflammatory
peripheral blood monocytes. Collagen-induced mediator in RA synovial tissues.
arthritis was suppressed in CCR9-deficient mice.
Inflammatory Increased CCR9 DSS-induced acute CCR9−/− mice are more susceptible to DSS colitis CCR9/CCL25 interaction regulates Wurbel et al.,
bowel disease and CCL25 colitis than WT littermate controls as shown by higher the inflammatory immune response of 2011
mortality, increased IBD score, and delayed the intestinal mucosa by balancing
recovery. During recovery, the CCR9−/− colonic different dendritic cell subsets.
mucosa is characterized by the accumulation of
activated macrophages and elevated levels of
Th1/Th17 inflammatory cytokines.
Inflammatory Increased CCR9 DSS-induced acute The mice lacking the interaction of CCR9/CCL25 CCR9/CCL25 interactions have Wurbel et al.,
bowel disease and CCL25 colitis showed enhanced adhesion promoting ability of protection against large intestinal 2014
coli after the transfer of naive T cells, and regulated inflammation in chronic colitis.
the pro-inflammatory and anti-inflammatory
subgroups of cDC.
Asthma Increased CCL25 OVA-induced model of In challenged CCR9-deficient mice, cell recruitment CCR9 and CCL25 expressions are Lopez-Pacheco
allergic inflammation was impaired at peribronchial and perivenular induced in the early stages of airway et al., 2016
within CCR9 deficient levels. OVA administration in CCR9-deficient mice inflammation and they have an
mice leads to a less inflammatory cell recruitment, which important role in modulating eosinophils
modifies the expression of IL-10, CCL11, and and lymphocytes recruitment at the first
CCL25 after OVA challenge. stages of inflammatory process.
Asthma Increased CCR9 NKT cells In patients with allergic asthma, the CCR9/CCL25 CCR9/CCL25 signal can interact with Sen et al., 2005
binding method selectively induces chemotaxis of CD226 signaling to activate asthmatic
NKT cells. And NKT cells may be in direct contact NKT cells, leading to airway
with CD3+ T cells, polarizing them to a Th2 bias. hyperresponsiveness and inflammation,
aggravating asthma.
Compelling evidence has indicated that alterations of CCR9 or CCL25 expression are also involved in inflammatory-associated diseases, including myocardial infarction,
hepatitis, rheumatoid arthritis, inflammatory bowel disease, and asthma.
CCR9, C-C chemokine receptor 9; CCL25, C-C chemokine ligand 25; RA, rheumatoid arthritis; IBD, inflammatory bowel disease; DSS, dextran sulfate sodium;
DCs, dendritic cells; IL-6, interleukin-6; IL-10, interleukin-10; MMP3, matrix metalloproteinase-3; TNF-α, tumor necrosis factor-α; NKT, natural killer T; DCs, dendritic
cells; Th, helper T.
bone marrow transplantation mouse models revealed that Primary sclerosing cholangitis (PSC), as a chronic
these CCR9+ CD11b+ macrophages were originated from bone inflammatory liver disease, is characterized by progressive
marrow-derived monocytes, but not liver resident macrophages. bile duct destruction and is also a parenteral complication of
In addition, in contact with hepatic stellate cells, these CD11b+ inflammatory bowel disease (IBD). In addition, PSC is a non-
inflammatory macrophages participated in the pathogenesis of suppurative autoimmune granulomatous inflammation of the
experimental liver fibrosis by knocking out CCR9 gene. The small bile ducts in the liver that can lead to chronic progressive
results with further verification in human samples clarified the cholestasis and eventually cirrhosis and liver failure (Chapman,
pathogenic role of CCR9/CCL25 axis as therapeutic target of a 1991). In the healthy liver, the expression of CCL25 is very
variety of liver diseases (Nakamoto, 2016). Similarly, Amiya et al. low or even undetected (Vicari et al., 1997; Zabel et al., 1999;
(2016) also demonstrated that in acute liver injury, inflammatory Eksteen et al., 2004). However, in PSC, the expression of CCL25
macrophages originated from bone marrow and became locally was increased in the liver, mainly through hepatic sinusoidal
differentiated and proliferation through interaction with hepatic endothelial cells and portal DCs expression (Eksteen et al., 2004).
stellate cells by knocking out CCR9 gene (Figure 2). The hepatic inflammation in PSC was related to the increase
Frontiers in Cell and Developmental Biology | www.frontiersin.org 5 August 2021 | Volume 9 | Article 686548Wu et al. Roles of CCR9/CCL25 in Inflammation of CCR9 positive T cells. Other study proposed that long-lived inhibited in CCR9−/− mice. CCR9 antagonist (CCX8037) memory gut homing cells that expressed CCR9 and α4 β7 and also suppressed collagen-induced arthritis and decreased the were early activated during episodes of IBD could exacerbate PSC migration of CD11b+ splenic cells to synovial tissues. These through interactions with hepatic endothelial that ectopically results suggested that the interaction between CCL25 and CCR9 expressed CCL25 (Eksteen et al., 2004). Notably, they also may promote cell infiltration and production of inflammatory demonstrated for the first time that T cells activated in the mediator in RA synovial tissues. Blocking CCL25 or CCR9 may intestine can be recruited to extra-intestinal site of disease in represent a strange new safety therapy for RA, and provide humans and provide basic research to explain the pathogenesis theoretical basis for further research a novel safe therapy for RA of extra-intestinal complications of IBD (Eksteen et al., 2004; (Yokoyama et al., 2014; Table 2). Table 2). Rheumatoid Arthritis Inflammatory Bowel Disease Rheumatoid arthritis (RA) is a chronic inflammatory disease that Inflammatory bowel disease is a group of chronic, non-specific can cause a large number of macrophages, T cells, and B cells to inflammatory bowel diseases whose etiology has not yet been accumulate in the synovium (Firestein, 1991; Kinne et al., 2000), clarified, mainly including ulcerative colitis (UC) and Crohn’s and the accumulation of these cells can further participate in disease (CD). UC is a continuous inflammation of the colonic the development of inflammation, joint destruction, and pain. mucosa and submucosa that first affects the rectum and gradually However, biological agents (TNF blockers and IL-6 receptor spreads to the entire colon. CD can affect the entire digestive tract antagonists) are effective in RA patients (Feldmann, 2002; and is a discontinuous full-layer inflammation, most commonly Nishimoto et al., 2004; Smolen et al., 2010). involving terminal ileum, colon, and perianal (Loftus, 2004; A large number of mononuclear/macrophages accumulate Molodecky et al., 2012). in the rheumatoid synovium, which play a promotive role in Wurbel et al. (2011) study the acute inflammation and inflammation and joint destruction. Identifying the molecules recovery in WT and CCR9−/− mice in a model of dextran involved in its accumulation and differentiation is essential for sulfate sodium (DSS)-induced colitis. The results show that the development of therapeutic strategies (Mulherin et al., 1996; CCL25 and CCR9 are both expressed in the large intestine Haringman et al., 2005; Nishimoto and Takagi, 2010). Cluster and are upregulated during DSS colitis. CCR9−/− mice are of differentiation (CD) 14 and CD68 co-localize with CCR9 or more susceptible to DSS colitis than WT littermate controls as CCL25 to identify macrophages. Other studies have confirmed shown by higher mortality, increased IBD score, and delayed that the augment CD68+ cells in the substratum of RA are one recovery. During recovery, the CCR9−/− colonic mucosa is of the characteristic pathological changes of synovial membrane characterized by the accumulation of activated macrophages in early RA (Singh et al., 2004). Other study demonstrated that and added Th1/Th17 inflammatory cytokines levels. Activated CCR9 was expressed by PB monocytes/macrophages in RA and plasmacytoid dendritic cells (pDC) accumulate in the mesenteric healthy donors, and increased in RA. Moreover, in the synovium lymph nodes of CCR9−/− animals, changing the local proportion of RA and non-RA patients, CCR9 colocates with CD14+ and of DC subsets. The T cells separate from these mesenteric lymph CD68+ macrophages and was more abundant in RA synovium. nodes were stimulated again, which were significantly higher Therefore, the percentage of CCR9+ monocytes in the synovium levels of TNF-α, IFN-γ, IL-2, IL-6, and IL-17A while down- of RA (81%) is increased compared to that in blood (40%), regulating IL-10 production (Figure 2). These results suggest and the percentage of CCR9+ monocytes in the synovium of that the CCR9/CCL25 interaction regulates the inflammatory non-RA (66%) is greater than that in blood (16%). Meanwhile, immune response of the intestinal mucosa by balancing different CCL25 could be detected in both RA and non-RA synovia, dendritic cell subsets (Wurbel et al., 2011). which can be co-localized within CD14+ and CD68+ cells As mentioned before, CCR9−/− and CCL25−/− mice are (Schmutz et al., 2010). Furthermore, CCL25 induced stronger more susceptible to acute DSS colitis than WT controls. As monocyte differentiation in RA. CCL25 induced significant human ulcerative colitis is associated with signs of chronic chemotaxis of peripheral blood monocytes, however, which was colonic inflammation, they investigated whether the increased inconsistent between different individuals. These results indicate susceptibility to acute inflammation associated with defective that monocyte-induced CCR9/CCL25 expression is significantly CCL25/CCR9 interactions would also translate into increased increased in RA. CCL25 may be involved in the differentiation susceptibility to chronic inflammation, and found that chronic of monocytes to macrophages particularly in RA (Haringman DSS exposure results in exacerbated colitis in mice deficient et al., 2005). Moreover, CCR9 and CCL25 are expressed at for either CCR9 or CCL25 when compared with WT control higher levels in RA synovial tissues compared to osteoarthritis mice. Although CCR9−/− T cells traffic to the colon and synovial tissues. Most CD68+ macrophages in RA synovial tissue induce severe colitis similar to WT T cells, naive WT T express CCR9 and CCL25 revealed by immunohistochemical. cells induce more severe disease in recipient animals devoid CCR9 was expressed in macrophage, fibroblast-like synoviocytes, of CCL25 expression. Moreover, compared with WT control and DCs of synovial tissues. CCL25 stimulated the production mice, there was no significant difference in the total number of IL-6 and MMP-3 in RA fibroblast-like synoviocytes, and of pDC and conventional dendritic cells (cDC), and the also increased the production of IL-6 and TNF-α in peripheral pro-inflammatory and anti-inflammatory subgroups of cDC blood monocytes (Figure 2). Collagen-induced arthritis was were regulated by the CCR9/CCL25 interaction. In the end, the Frontiers in Cell and Developmental Biology | www.frontiersin.org 6 August 2021 | Volume 9 | Article 686548
Wu et al. Roles of CCR9/CCL25 in Inflammation
CCR9/CCL25-dependent innate immune cell lineage specificity anti-inflammatory chemokine, was significantly reduced (more
and lineage-dependent function will be remarkably assisted than 60%). In addition, there was an increase in the expression
via targeting the loss of CCR9/CCL25 in innate immune cell of CCL25 in the WT mice as early as 6 h after ova-challenge.
and/or epithelial compartment. These results suggested that Meanwhile, CCL25 expression was decreased at all time test
CCR9/CCL25 interactions have protection against large intestinal in CCR9−/− mice (Figure 2). The above results confirm that
inflammation in chronic colitis (Wurbel et al., 2014). Moreover, CCR9 deficiency has a positive regulatory effect on eosinophils
Papadakis et al. (2001) demonstrated that the proportion and lymphocytes in the early stage of inflammation induction,
of peripheral blood CCR9+ CD4+ cells rose remarkably in suggesting that they may be potential targets for regulating
active small bowel CD compared with normal groups, but not asthma inflammation in asthma (Lopez-Pacheco et al., 2016).
in patients with purely colonic Crohn’s. It is worth noting Natural killer T (NKT) cells are the main operators in
that GSK/Chemocentryx has advanced its CCR9 antagonist the development of asthma. Multiple NKT cells migrate and
CCX282-B (also known as vercirnon) to a pivotal phase III aggregate in the airway, producing a Th2 bias effect that directly
clinical trial. It was unfortunate that due to poor efficacy of or indirectly promotes asthma. Studies have found that the
IBD, the clinical project was terminated at the end of 2013 recruitment of NKT cells depends on the high expression of
(Zhang et al., 2015). CCR9 and the connection of CCR9/CCL25 (DeKruyff et al.,
The pathophysiological characteristics of necrotizing 2014; Griffith et al., 2014). In patients with allergic asthma, the
enterocolitis (NEC) include excessive inflammation and necrosis, CCR9/CCL25 binding method selectively induces chemotaxis
which can affect any part of the gastrointestinal tract (especially of NKT cells, whereas in healthy volunteers, normal NKT cells
the small intestine) (Neu and Walker, 2011; Nino et al., 2016). are not able to induce. Further studies have confirmed that the
The imbalance caused by the decrease in tolerogenic Foxp3+ pathways for NKT cells regulate the development of asthma. In
regulatory T (Treg) cells and the increase in the production the process of migrating from blood vessels to airway bronchial
of Th17 cells in the lamina propria pro-inflammatory il-17 mucosa, NKT cells may directly contact CD3+ T cells, making
leads to the NEC-induced excessive inflammatory response them polarized toward Th2. This regulatory function depends
(Weitkamp et al., 2013; Liu et al., 2014; Egan et al., 2016). on DC participation and CCR9/CD226 coordinated activation.
Moreover, another study has shown that in the peripheral blood The adhesion molecule CD226 is overexpressed in asthmatic
of NEC patients and mice, the proportion of CCR9+ CD4+ NKT cells. The CCR9/CCL25 linkage can directly phosphorylate
T cells was significantly elevated. Increased CCR9+ CD4+ T CD226, and the lack of CD226 can block the Th2 bias effect
cells were mainly CCR9+ IL-17-producing Treg cells, which are induced by NKT cells. These results indicate that CCR9/CCL25
characteristic of common Treg cells, but their inhibitory activities signaling pathway could interact with CD226 signals to activate
were seriously damaged and passively correlated with the serious asthmatic NKT cells, leading to airway hyperresponsiveness
of intestinal tissue injury. Treg cells that produce CCR9+ IL-17 and inflammation, aggravating asthma (Sen et al., 2005). In
may be an important biomarker, improving NEC by regulating addition, Castan et al. (2018) demonstrated that CCR9 knock-
the balance of lymphocytes (Ma et al., 2019). In summary, these out mice eliminated the aggravation of lung symptoms in
results demonstrated that CCR9+ IL-17-producing Treg cells consecutive food and respiratory allergies, which were featured
could be an important biomarker, but further research is needed by a rose in lung resistance and a higher Th17/Treg ratio in
for clinical use (Table 2). solely asthmatic-like mice. Moreover, to better understand the
mechanism underlying the food allergy-induced aggravation of
Asthma asthma and the role of CCR9, they performed adoptive transfer
Asthma, as a lung disease, is characterized by reversible of CD4+ T cells from food-allergic mice into naïve mice,
airway obstruction, airway inflammation, and increased airway which were subsequently sensitized to house dust mites. They
responsiveness to a variety of stimuli (Hahn, 2009; Mims, found that asthmatic mice received food-sensitized CD4+ T cells
2015). Chemokine receptors have been confirmed to be and had more severe inflammation than asthmatic mice that
involved in leukocyte recruitment, and are closely related to received non-sensitized CD4+ T cells. Interestingly, when mice
asthma pathology (DeKruyff et al., 2014; Griffith et al., 2014). received food allergen-sensitized lymphocytes from CCR9−/−
An ovalbumin (OVA)-induced allergic inflammation model mice, the exacerbation of asthma caused by food allergen CD4+
was established in CCR9−/− mice, and the expression of lymphocytes was eliminated. These results show that CCR9 is a
CCR9 and CCL25 in eosinophils and T lymphocytes was driving factor for the worsening of lung inflammation in food
found 6 h post-OVA challenge. Meanwhile, compared with allergic mice (Castan et al., 2018), and confirm its application
wild-type mice, the peribronchial infiltration in CCR9-deficient potential in the development of treatment strategies for allergic
mice was significantly reduced (nearly 50%), while the total diseases (Table 2).
number of eosinophils recruited in bronchoalveolar fluid (BALF)
was decreased (30%). Moreover, in CCR9−/− mice, OVA Autoimmune Diseases
administration can reduce the recruitment of inflammatory Toll-like receptor 4 (TLR4) is an important part of innate
cell, which modifies IL-10, CCL11, and CCL25 expression at immunity and has been linked to central nervous system
24 h after OVA (Lopez-Pacheco et al., 2016). Interestingly, (CNS) inflammatory diseases (Ureña-Peralta et al., 2020). Zhang
expression of TGF-β and IL-17 was elevated in OVA-stimulated et al. (2019) have shown that TLR4−/− mice were inadequate
CCR9-deficient mice compared to WT mice, whereas IL-10, as an to induce experimental autoimmune encephalomyelitis (EAE),
Frontiers in Cell and Developmental Biology | www.frontiersin.org 7 August 2021 | Volume 9 | Article 686548Wu et al. Roles of CCR9/CCL25 in Inflammation
which is featured by reducing low clinic score, weight loss, the digestive system (McGuire et al., 2011). The CCR9 signal
demyelinating, and spinal cord inflammatory cell infiltration. transmitted during the startup of naïve T cells promotes the
The deletion of TLR4 in the lesion area of EAE mice can differentiation of memory CD4+ T cells that produce α 4
decrease inflammatory cytokines and CCL25 secretion. After β + 7 IFN-γ, increasing the immune microenvironment in
transformation, CCR9 expression is reduced in TLR4−/− gastrointestinal tissues, thereby affecting effector immunity
Th17 cells, and the chemotaxis and migration ability are in infections and cancer (Fu et al., 2019). Notably, Chen
weakened. In summary, TLR4 may play an important role in et al. (2020) used tumor acidity-responsive nanoparticle
the infiltration of Th17 during the pathogenesis of EAE by delivery system (NP-siCD47/CCL25) to discharge CCL25
CCL25/CCR9 signaling pathway (Zhang et al., 2019). Kadowaki protein and CD47 siRNA in tumors to enhance CD47
et al. (2019) also demonstrate that in the mice model of targeted immunotherapy.
experimental autoimmune encephalomyelitis, CCR9+ memory In the study, NP-siCD47/CCL25 remarkably increased the
T cells preferentially infiltrate the inflammatory CNS and invasiveness of CCR9+ CD8+ T cells, inhibited the expression
express lymphocyte activation 3 gene (LAG3) in the late of CD47 in tumor cells, and inhibited tumor cells metastasis
stage. Antibiotic treatment can alleviate the symptoms of and growth by T-cell-dependent immunity (Chen et al., 2020).
experimental autoimmune encephalomyelitis, which is supported In addition, Khandelwal et al. (2015) pointed out that CCR9
by a significant rise in peripheral blood CCR9+ memory T regulates the STAT signal in T cells and inhibits the secretion
cells. Generally speaking, they postulate that the alterations in and cytotoxicity of T lymphocytes type 1 cytokines. This
CCR9+ memory T cells observed, caused by either the gut study shows that inhibiting CCR9 expression may promote
microbiota changes or ageing, may lead to the development of tumor-specific T cell immunotherapy (Khandelwal et al., 2015).
secondary progressive multiple sclerosis (Kadowaki et al., 2019). In conclusion, targeting CCR9/CCL25 is expected to be a new
Moreover, the CCL25/CCR9 was also powerful to authorize approach for treating tumors, by suppressing or treating tumor
effector/memory T cells to access anatomic sites (Evans-Marin patients with an autoimmune system that produces a lasting
et al., 2015). Binding of CCR9 to CCL25 inhibits CD4 T cells antitumor response.
differentiating to Tregs. In autoimmunity, CCR9+ T helper cells
induce diabetes by secreting IL-21 and promote the expansion
and survival of CD8t cells (McGuire et al., 2011). CONCLUSION AND POTENTIAL FUTURE
Omenn syndrome is resulted from a mild rag mutation, DIRECTIONS
which is featured by severe immunodeficiency and similar
manifestations of autoimmunity (Villa et al., 1998; Khiong et al., Inflammatory diseases have become a serious threat to the
2007). Rigoni et al. (2016) confirmed that long-term use of health of the global population. Inflammatory diseases involve
broad-spectrum antibiotics in Rag2 (R229Q) mice can ameliorate lesions of multiple tissues and organs in the body, which
intestinal and systemic autoimmunity by reducing mucosal and are characterized by tissue damage caused by excessive or
circulating gut-tropic CCR9(+) Th1 and Th17 T cells frequency. persistent inflammation, such as CVD, hepatitis, asthma, RA,
In addition, during the allergic reaction, CCL25 drives the and inflammatory bowel diseases. However, the common
mobilization of IL-17+ γδ T cells to inflamed tissues through features of these diseases are abnormal regulation of
α4β7 integrin, and regulates the level of IL-17 (Costa et al., inflammatory response and imbalance of immune pathways.
2012). The above studies have proved that CCR9/CCL25 plays an Chemokines are a family of small molecule cytokines
important role in autoimmune diseases. whose receptors are seven-transmembrane glycoproteins,
mainly expressed on the surface of inflammatory cells.
Cancer Previous studies have shown that as members of the
In microenvironment, tumor formation and immune system chemokine CC subfamily, CCR9 and CCL25 have been
are mutually restricted, and chemokines also play an important related to various inflammatory diseases as well as could
role between tumor formation and immune system (Fan et al., promote inflammatory responses. Recently, the roles of
2019; Rossi et al., 2019; Lei et al., 2020). T cells are one of the CCR9/CCL25 in inflammation and related diseases have
main functional cells of the anti-cancer immune response. CD4+ become clearer. CCR9/CCL25 is participated in many
T cells have an important regulatory effect, and CD8+ T cell inflammatory diseases, including CVD, hepatitis, RA, IBD,
stem cell-like subgroups have the potential to self-proliferate and and asthma (Table 2). Although the functional studies
differentiate toward effector cells, which can produce durable regarding CCR9/CCL25 in inflammatory diseases have gradually
anti-tumor immune response and specifically kill tumor cells deepened, the understanding of CCR9/CCL25 has become
(Borst et al., 2018; Farhood et al., 2019; He et al., 2019; Brightman more comprehensive. However, studies on the mechanisms
et al., 2020). of CCR9/CCL25 underlying inflammatory diseases are
Studies have found that T cell function depends on mostly restricted to the theoretical basic, and their clinical
the expression of CCR9. CD4+ CCR9+ T helper cells application is few.
express high amounts of interleukin 21 and induce Although several lines of evidence have clarified
T cell costimulatory factor, transcription factor B cell the specific mechanism of CCR9/CCL25 signaling in
CLL/lymphoma 6 (Bcl-6), and Maf, which are local features inflammation-associated diseases, the development of successful
of autoimmune diseases that affect the accessory organs of treatment of CCR9/CCL25 is still in further study stage.
Frontiers in Cell and Developmental Biology | www.frontiersin.org 8 August 2021 | Volume 9 | Article 686548Wu et al. Roles of CCR9/CCL25 in Inflammation
CCX282-B is bioavailable in the circulation following oral proposes a new underlying therapeutic mechanisms and target
administration, and which has high specificity for CCR9 with for the future treatment of inflammatory diseases.
negligible binding to any other chemokine receptor, have been
evaluated in murine models of IBD as well as in clinical trials.
Meanwhile, related studies have confirmed that the use of an AUTHOR CONTRIBUTIONS
oral antagonist for CCR9 (CCX282-B) was also evaluated in
phase II and phase III clinical trials with mixed results, but the XW and MS: conceptualization, literature search, and
results were not as expected. Therefore, to make further progress original draft writing and editing. ZY, CL, QW, HW, and
in delineating the potential clinical role of CCR9 in human CD: original draft writing and editing. YL and YY:
disease, detailed mechanistic studies and well-designed proof- conceptualization, original draft writing and editing, supervision,
of-concept human trials are now required. Further investigation and funding acquisition. All authors contributed to the article
is likely to focus on (1) studying the effects of blocking CCR9 and approved the submitted version.
on the activation state of circulating and tissue-infiltrating
lymphocytes, (2) investigating disease remission in CD remains
a strong indication for CCR9 antagonist treatment, and any FUNDING
future clinical trials should include patients with UC and with
PSC, (3) investigating whether the clinical application of CCR9 This work was supported by the Key R&D Plans of Shaanxi
antagonism has any suboptimum efficacy, and (4) continuing to Province (2021SF-317 and 2021SF-075), Science and Technology
study CCR9/CCL25 upstream and downstream molecules, which Plan Project of Yulin City (YF-2020-191 and CXY-2020-098),
are possible future potential therapeutic targets for inflammatory National Natural Science Foundation of China (81871607,
diseases. In conclusion, this review presents a comprehensive 82070422, and 81700236), and Natural Science Foundation of
picture of the role of CCR9/CCL25 in inflammatory diseases and Shaanxi Province (2020JM-386 and 2018JM3042).
REFERENCES Egan, C. E., Sodhi, C. P., Good, M., Lin, J., Jia, H., and Yamaguchi, Y.
(2016). Toll-like receptor 4-mediated lymphocyte influx induces neonatal
Amiya, T., Nakamoto, N., Chu, P. S., Teratani, T., Nakajima, H., and Fukuchi, necrotizing enterocolitis. J Clin. Invest. 126, 495–508. doi: 10.1172/jci
Y. (2016). Bone marrow-derived macrophages distinct from tissue-resident 83356
macrophages play a pivotal role in Concanavalin A-induced murine liver injury Eksteen, B., Grant, A. J., Miles, A., Curbishley, S. M., Lalor, P. F., and Hubscher,
via CCR9 axis. Sci Rep. 6, 35146. S. G. (2004). Hepatic endothelial CCL25 mediates the recruitment of CCR9+
Bleul, C. C., Farzan, M., Choe, H., Parolin, C., Clark-Lewis, I., Sodroski, gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp.
J., et al. (1996). The lymphocyte chemoattractant SDF-1 is a ligand for Med. 200, 1511–1517. doi: 10.1084/jem.20041035
LESTR/fusin and blocks HIV-1 entry. Nature. 382, 829–833. doi: 10.1038/3828 Evans-Marin, H. L., Cao, A. T., Yao, S., Chen, F., He, C., and Liu, H. (2015).
29a0 Unexpected Regulatory Role of CCR9 in Regulatory T Cell Development. PLoS
Borst, J., Ahrends, T., Ba̧bała, N., Melief, C. J. M., and Kastenmüller, W. (2018). One. 10:e0134100. doi: 10.1371/journal.pone.0134100
CD4(+) T cell help in cancer immunology and immunotherapy. Nat Rev. Fan, L., Li, Y., Chen, J. Y., Zheng, Y. F., and Xu, X. M. (2019). Immune
Immunol. 18, 635–647. doi: 10.1038/s41577-018-0044-0 checkpoint modulators in cancer immunotherapy: Recent advances and
Brightman, S. E., Naradikian, M. S., Miller, A. M., and Schoenberger, S. P. (2020). combination rationales. Cancer Lett. 456, 23–28. doi: 10.1016/j.canlet.2019.0
Harnessing neoantigen specific CD4 T cells for cancer immunotherapy. J 3.050
Leukoc. Biol. 107, 625–633. doi: 10.1002/jlb.5ri0220-603rr Farhood, B., Najafi, M., and Mortezaee, K. (2019). CD8(+) cytotoxic T lymphocytes
Castan, L., Cheminant, M. A., Colas, L., Brouard, S., Magnan, A., and Bouchaud, in cancer immunotherapy: A review. J Cell Physiol. 234, 8509–8521. doi: 10.
G. (2018). Food allergen-sensitized CCR9(+) lymphocytes enhance airways 1002/jcp.27782
allergic inflammation in mice. Allergy 73, 1505–1514. doi: 10.1111/all.1 Feldmann, M. (2002). Development of anti-TNF therapy for rheumatoid arthritis.
3386 Nat Rev. Immunol. 2, 364–371. doi: 10.1038/nri802
Chapman, R. W. (1991). Aetiology and natural history of primary sclerosing Firestein, G. S. (1991). The immunopathogenesis of rheumatoid arthritis. Curr
cholangitis–a decade of progress? Gut. 32, 1433–1435. doi: 10.1136/gut.32.12. Opin. Rheumatol. 3, 398–406. doi: 10.1097/00002281-199106000-00012
1433 Fu, H., Jangani, M., Parmar, A., Wang, G., Coe, D., and Spear, S. (2019). A Subset of
Chen, H., Cong, X., Wu, C., Wu, X., Wang, J., Mao, K., et al. (2020). Intratumoral CCL25-Induced Gut-Homing T Cells Affects Intestinal Immunity to Infection
delivery of CCL25 enhances immunotherapy against triple-negative breast and Cancer. Front Immunol. 10:271.
cancer by recruiting CCR9(+) T cells. Science Advances 6, 4690. Griffith, J. W., Sokol, C. L., and Luster, A. D. (2014). Chemokines and chemokine
Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C., and Lusso, receptors: positioning cells for host defense and immunity. Annu Rev. Immunol.
P. (1995). Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major 32, 659–702. doi: 10.1146/annurev-immunol-032713-120145
HIV-suppressive factors produced by CD8+ T cells. Science. 270, 1811–1815. Guo, H., Callaway, J. B., and Ting, J. P. (2015). Inflammasomes: mechanism of
doi: 10.1126/science.270.5243.1811 action, role in disease, and therapeutics. Nat. Med. 21, 677–687. doi: 10.1038/
Costa, M. F., Bornstein, V. U., Candéa, A. L., Henriques-Pons, A., Henriques, nm.3893
M. G., and Penido, C. (2012). CCL25 induces α4β7 integrin-dependent Hadeiba, H., Lahl, K., Edalati, A., Oderup, C., Habtezion, A., and Pachynski, R.
migration of IL-17+ γδ T lymphocytes during an allergic reaction. Eur J. (2012). Plasmacytoid dendritic cells transport peripheral antigens to the thymus
Immunol. 42, 1250–1260. doi: 10.1002/eji.201142021 to promote central tolerance. Immunity. 36, 438–450. doi: 10.1016/j.immuni.
Crispe, I. N. (2003). Hepatic T cells and liver tolerance. Nat Rev. Immunol. 3, 51–62. 2012.01.017
doi: 10.1038/nri981 Hahn, D. L. (2009). Importance of evidence grading for guideline implementation:
DeKruyff, R. H., Yu, S., Kim, H. Y., and Umetsu, D. T. (2014). Innate immunity the example of asthma. Ann. Fam Med. 7, 364–369. doi: 10.1370/afm.995
in the lung regulates the development of asthma. Immunol. Rev. 260, 235–248. Haringman, J. J., Gerlag, D. M., Zwinderman, A. H., Smeets, T. J., Kraan, M. C.,
doi: 10.1111/imr.12187 and Baeten, D. (2005). Synovial tissue macrophages: a sensitive biomarker for
Frontiers in Cell and Developmental Biology | www.frontiersin.org 9 August 2021 | Volume 9 | Article 686548Wu et al. Roles of CCR9/CCL25 in Inflammation response to treatment in patients with rheumatoid arthritis. Ann Rheum. Dis. Mulherin, D., Fitzgerald, O., and Bresnihan, B. (1996). Synovial tissue macrophage 64, 834–838. doi: 10.1136/ard.2004.029751 populations and articular damage in rheumatoid arthritis. Arthritis. Rheum. 39, He, Q. F., Xu, Y., Li, J., Huang, Z. M., Li, X. H., and Wang, X. (2019). CD8+ T-cell 115–124. doi: 10.1002/art.1780390116 exhaustion in cancer: mechanisms and new area for cancer immunotherapy. Nakamoto, N. (2016). Role of inflammatory macrophages and CCR9/CCL25 Brief. Funct Genomics. 18, 99–106. doi: 10.1093/bfgp/ely006 chemokine axis in the pathogenesis of liver injury as a therapeutic target. Nihon Huang, Y., Wang, D., Wang, X., Zhang, Y., Liu, T., and Chen, Y. (2016). Abrogation Rinsho. Meneki. Gakkai Kaishi. 39, 460–467. doi: 10.2177/jsci.39.460 of CC chemokine receptor 9 ameliorates ventricular remodeling in mice after Nakamoto, N., Ebinuma, H., Kanai, T., Chu, P. S., Ono, Y., and Mikami, Y. myocardial infarction. Sci Rep. 6, 32660. (2012). CCR9+ macrophages are required for acute liver inflammation in mouse Igaki, K., Komoike, Y., Nakamura, Y., Watanabe, T., Yamasaki, M., and Fleming, P. models of hepatitis. Gastroenterology. 142, 366–376. doi: 10.1053/j.gastro.2011. (2018). MLN3126, an antagonist of the chemokine receptor CCR9, ameliorates 10.039 inflammation in a T cell mediated mouse colitis model. Int. Immunopharmacol. Nino, D. F., Sodhi, C. P., and Hackam, D. J. (2016). Necrotizing enterocolitis: new 60, 160–169. doi: 10.1016/j.intimp.2018.04.049 insights into pathogenesis and mechanisms. Nat Rev Gastroenterol Hepatol. 13, Jokinen, E. (2015). Obesity and cardiovascular disease. Minerva. Pediatr. 67, 25–32. 590–600. doi: 10.1038/nrgastro.2016.119 Kadowaki, A., Saga, R., Lin, Y., Sato, W., and Yamamura, T. (2019). Nishimoto, N., and Takagi, N. (2010). Safety and efficacy profiles of tocilizumab Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of progressive multiple sclerosis. Brain. 142, 916–931. doi: 10.1093/brain/awz012 six initial trials and five long-term extensions. Mod Rheumatol. 20, 222–232. Kalindjian, S. B., Kadnur, S. V., Hewson, C. A., Venkateshappa, C., Juluri, S., and doi: 10.3109/s10165-010-0279-5 Kristam, R. (2016). A New Series of Orally Bioavailable Chemokine Receptor 9 Nishimoto, N., Yoshizaki, K., Miyasaka, N., Yamamoto, K., Kawai, S., and Takeuchi, (CCR9) Antagonists; Possible Agents for the Treatment of Inflammatory Bowel T. (2004). Treatment of rheumatoid arthritis with humanized anti-interleukin- Disease. J Med. Chem. 59, 3098–3111. doi: 10.1021/acs.jmedchem.5b01840 6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Khandelwal, N., Breinig, M., Speck, T., Michels, T., Kreutzer, C., and Sorrentino, A. Arthritis Rheum. 50, 1761–1769. doi: 10.1002/art.20303 (2015). A high-throughput RNAi screen for detection of immune-checkpoint Oberlin, E., Amara, A., Bachelerie, F., Bessia, C., Virelizier, J. L., and Arenzana- molecules that mediate tumor resistance to cytotoxic T lymphocytes. EMBO. Seisdedos, F. (1996). The CXC chemokine SDF-1 is the ligand for LESTR/fusin Mol. Med. 7, 450–463. doi: 10.15252/emmm.201404414 and prevents infection by T-cell-line-adapted HIV-1. Nature. 382, 833–835. Khiong, K., Murakami, M., Kitabayashi, C., Ueda, N., Sawa, S., and Sakamoto, doi: 10.1038/382833a0 A. (2007). Homeostatically proliferating CD4 T cells are involved in the Papadakis, K. A., Landers, C., Prehn, J., Kouroumalis, E. A., Moreno, S. T., and pathogenesis of an Omenn syndrome murine model. J Clin. Invest. 117, 1270– Gutierrez-Ramos, J. C. (2003). CC chemokine receptor 9 expression defines 1281. doi: 10.1172/jci30513 a subset of peripheral blood lymphocytes with mucosal T cell phenotype and Kinne, R. W., Brauer, R., Stuhlmuller, B., Palombo-Kinne, E., and Burmester, G. R. Th1 or T-regulatory 1 cytokine profile. J. Immunol. 171, 159–165. doi: 10.4049/ (2000). Macrophages in rheumatoid arthritis. Arthritis. Res. 2, 189–202. jimmunol.171.1.159 Kunkel, E. J., Campbell, J. J., Haraldsen, G., Pan, J., Boisvert, J., and Roberts, Papadakis, K. A., Prehn, J., Moreno, S. T., Cheng, L., Kouroumalis, E. A., and Deem, A. I. (2000). Lymphocyte CC chemokine receptor 9 and epithelial thymus- R. (2001). CCR9-positive lymphocytes and thymus-expressed chemokine expressed chemokine (TECK) expression distinguish the small intestinal distinguish small bowel from colonic Crohn’s disease. Gastroenterology. 121, immune compartment: Epithelial expression of tissue-specific chemokines as 246–254. doi: 10.1053/gast.2001.27154 an organizing principle in regional immunity. J Exp. Med. 192, 761–768. doi: Papadakis, K. A., Prehn, J., Nelson, V., Cheng, L., Binder, S. W., and Ponath, 10.1084/jem.192.5.761 P. D. (2000). The role of thymus-expressed chemokine and its receptor CCR9 Lei, X., Lei, Y., Li, J. K., Du, W. X., Li, R. G., and Yang, J. (2020). Immune cells on lymphocytes in the regional specialization of the mucosal immune system. within the tumor microenvironment: Biological functions and roles in cancer J. Immunol. 165, 5069–5076. doi: 10.4049/jimmunol.165.9.5069 immunotherapy. Cancer. Lett. 470, 126–133. doi: 10.1016/j.canlet.2019.11.009 Qiuping, Z., Jei, X., Youxin, J., Wei, J., Chun, L., and Jin, W. (2004). CC chemokine Liu, Y., Tran, D. Q., Fatheree, N. Y., and Marc Rhoads, J. (2014). Lactobacillus ligand 25 enhances resistance to apoptosis in CD4+ T cells from patients reuteri DSM 17938 differentially modulates effector memory T cells and Foxp3+ with T-cell lineage acute and chronic lymphocytic leukemia by means of livin regulatory T cells in a mouse model of necrotizing enterocolitis. Am J. Physiol. activation. Cancer Res. 64, 7579–7587. doi: 10.1158/0008-5472.can-04-0641 Gastrointest. Liver Physiol. 307, G177–G186. Rigoni, R., Fontana, E., Guglielmetti, S., Fosso, B., D’Erchia, A. M., and Maina, V. Loftus, E. V. Jr. (2004). Clinical epidemiology of inflammatory bowel disease: (2016). Intestinal microbiota sustains inflammation and autoimmunity induced Incidence, prevalence, and environmental influences. Gastroenterology. 126, by hypomorphic RAG defects. J Exp. Med. 213, 355–375. doi: 10.1084/jem. 1504–1517. doi: 10.1053/j.gastro.2004.01.063 20151116 Lopez-Pacheco, C., Soldevila, G., Du Pont, G., Hernandez-Pando, R., and Garcia- Rivera-Nieves, J., Ho, J., Bamias, G., Ivashkina, N., Ley, K., Oppermann, M., Zepeda, E. A. (2016). CCR9 Is a Key Regulator of Early Phases of Allergic et al. (2006). Antibody blockade of CCL25/CCR9 ameliorates early but not late Airway Inflammation. Mediators Inflamm 2016, 3635809. chronic murine ileitis. Gastroenterology. 131, 1518–1529. doi: 10.1053/j.gastro. Ma, F., Li, S., Gao, X., Zhou, J., Zhu, X., and Wang, D. (2019). Interleukin-6- 2006.08.031 mediated CCR9(+) interleukin-17-producing regulatory T cells polarization Rossi, J. F., Céballos, P., and Lu, Z. Y. (2019). Immune precision medicine for increases the severity of necrotizing enterocolitis. EBioMedicine. 44, 71–85. cancer: a novel insight based on the efficiency of immune effector cells. Cancer doi: 10.1016/j.ebiom.2019.05.042 Commun. (Lond). 39, 34. doi: 10.1186/s40880-019-0379-3 Malani, P. N. (2017). Hepatitis A. JAMA. 318, 2393. Schmutz, C., Cartwright, A., Williams, H., Haworth, O., Williams, J. H., and Marti, L. C. (2015). Chemokines and immunity. Einstein (São Paulo). 13, 469–473. Filer, A. (2010). Monocytes/macrophages express chemokine receptor CCR9 in McGuire, H. M., Vogelzang, A., Ma, C. S., Hughes, W. E., Silveira, P. A., and rheumatoid arthritis and CCL25 stimulates their differentiation. Arthritis Res. Tangye, S. G. (2011). A subset of interleukin-21+ chemokine receptor CCR9+ Ther. 12, R161. T helper cells target accessory organs of the digestive system in autoimmunity. Schulz, O., Hammerschmidt, S. I., Moschovakis, and Forster, R. (2016). Immunity. 34, 602–615. doi: 10.1016/j.immuni.2011.01.021 Chemokines and Chemokine Receptors in Lymphoid Tissue Dynamics. Annu Mims, J. W. (2015). Asthma: definitions and pathophysiology. Int Forum. Allergy Rev. Immunol. 34, 203–242. doi: 10.1146/annurev-immunol-041015-055649 Rhinol. 5 Suppl 1, S2–S6. Sen, Y., Yongyi, B., Yuling, H., Luokun, X., Li, H., and Jie, X. (2005). V alpha 24- Molodecky, N. A., Soon, I. S., Rabi, D. M., Ghali, W. A., Ferris, M., and Chernoff, G. invariant NKT cells from patients with allergic asthma express CCR9 at high (2012). Increasing incidence and prevalence of the inflammatory bowel diseases frequency and induce Th2 bias of CD3+ T cells upon CD226 engagement. with time, based on systematic review. Gastroenterology 142, 46–54.e42;quiz J. Immunol. 175, 4914–4926. doi: 10.4049/jimmunol.175.8.4914 e30. Singh, J. A., Pando, J. A., Tomaszewski, J., and Schumacher, H. R. (2004). Moser, B., Wolf, M., Walz, A., and Loetscher, P. (2004). Chemokines: multiple Quantitative analysis of immunohistologic features of very early rheumatoid levels of leukocyte migration control. Trends. Immunol. 25, 75–84. doi: 10. synovitis in disease modifying antirheumatic drug- and corticosteroid-naive 1016/j.it.2003.12.005 patients. J. Rheumatol. 31, 1281–1285. Frontiers in Cell and Developmental Biology | www.frontiersin.org 10 August 2021 | Volume 9 | Article 686548
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